Back to resultsA Study of LY2334737 in Participants With Cancer That is Advanced and/or Has Spread
Primary Purpose
Malignant Solid Tumor, Solid Tumor, Metastatic Tumor
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
LY2334737
Sponsored by
About this trial
This is an interventional treatment trial for Malignant Solid Tumor
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of advanced and/or metastatic cancer (including lymphoma) for which no treatment of higher priority exists
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
- Estimated life expectancy of more than 12 weeks
- Have discontinued all previous therapies for cancer for at least 30 days (6 weeks for mitomycin-C or nitrosoureas) and recovered from acute effects of therapy
- Have discontinued radiotherapy more than one week before enrolling in the study and have recovered from the acute effects of therapy
- Have adequate organ function
- Follow your doctor's directions and live close enough to the study site so you can continue to go to the clinic for follow-up
- Are willing and able to swallow capsules and follow study procedures
- Have given written informed consent prior to any study-specific procedures
- Males and females with reproductive potential should use medically approved contraceptive precautions during the study and for 6 months following the last dose of study drug
- Females with child-bearing potential must have had a negative urine or serum pregnancy test 7 days prior to the first dose of study drug
Exclusion Criteria:
- Have gastrointestinal diseases or prior surgery that may interfere with the absorption of medication taken by mouth
- Females who are pregnant or lactating
- Symptomatic central nervous system malignancy or metastasis
- Known positive test results in human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb)
- Liver cirrhosis or chronic hepatitis
- Acute or chronic leukemia
- Are currently receiving treatment with valproic acid (VPA) and its derivatives, or if you have a history of intolerance to VPA
- Known hypersensitivity to gemcitabine
Sites / Locations
- For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
- For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
- For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
- For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
LY2334737 - Arm A
LY2334737 - Arm B
Arm Description
LY2334737 administered orally at escalating doses [40 milligrams (mg) - 200 mg] every other day for 21 days followed by 7 days without study drug (28 day treatment cycle). Participants may receive additional treatment cycles until discontinuation criterion is met.
LY2334737 administered orally at escalating doses (40 mg - 200 mg) every day for 7 days followed by 7 days without study drug then repeated (28 day treatment cycle). Participants may receive additional treatment cycles until discontinuation criterion is met.
Outcomes
Primary Outcome Measures
Recommended Dose for Phase 2 Studies
Recommended Phase 2 dose was determined by maximum tolerated dose (MTD). The MTD was the highest dose level at which <2 out of 6 participants experienced a dose-limiting toxicity (DLT) in Cycle 1. DLT was an adverse event (AE) during Cycle 1 that was likely related to LY2334737 and fulfilled any of the following criteria: Common Terminology Criteria for Adverse Events (CTCAE) ≥Grade 3 nonhematological (except nausea/vomiting controlled with treatment); Grade 3 neutropenia with fever or any Grade 4 neutropenia with or without fever; Grade 3 thrombocytopenia with ≥Grade 2 bleeding or Grade 4 thrombocytopenia with or without bleeding; A recovery period longer than 14 days from last dose of LY2334737 to values allowing Cycle 2 to start; Other significant drug-related toxicity deemed by investigator to be dose limiting or that caused the participant to withdraw from the study. Pharmacokinetics and pharmacodynamics (PK/PD) were also taken into consideration for Phase 2 recommended dose.
Secondary Outcome Measures
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for LY2334737
AUC over the dosing interval (AUC0-Ƭ) of LY2334737 for Arm A (single dose) is 0 to 48 hours postdose. AUC0-Ƭ of LY2334737 for Arm B (multiple doses) is 0 to 24 hours postdose and AUC time 0 to infinity (AUC0-∞) for LY2334737.
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for 2'2'-Difluorodeoxycytidine (dFdC)
AUC over the dosing interval (AUC0-Ƭ) of dFdC (a metabolite of LY2334737) for Arm A (following a single dose of LY2334737) AUC0-Ƭ is 0-48 hours postdose, Arm B (following multiple doses of LY2334737) AUC 0-Ƭ is 0-24 hours postdose and AUC from time 0 to infinity (AUC0-∞).
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for Difluorodeoxyuridine (dFdU)
Daily AUC from time 0 to 24 hours (AUC 0-24) of dFdU (a metabolite of LY2334737) for Arm A (single dose of LY2334737) and Arm B (multiple doses of LY2334737).
Pharmacokinetics: Maximum Plasma Concentration (Cmax)
Cmax for LY2334737 and its metabolites 2'2'-difluorodeoxycytidine (dFdC) and difluorodeoxyuridine (dFdU).
Number of Participants With Best Overall Response (BOR)
Response defined using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria. Complete Response defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Partial Response defined as ≥30% decrease in sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD) defined as ≥20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions, or appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Stable Disease was defined as small changes that did not meet above criteria and unknown defined as response status was not known. The BOR was the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).
Progression-Free Survival (PFS)
PFS was defined as the time from date of first dose to the first observation of disease progression or death due to any cause.
Due to the different tumor types, schedules and doses, the PFS was not analyzed.
Percentage of Participants With Changes in QT Interval (>30 Milliseconds) From Baseline
Fridericia-corrected QT (QTcF) interval corrected for heart rate was assessed using triplicate 12-lead electrocardiograms (ECGs). Change in QT interval from baseline was calculated using a time matched approach, that is change from baseline was calculated by subtracting the respective reading taken at the same nominal time on Day-1 from the reading taken on Days 1 and 21; change from baseline was calculated by subtracting the last non-missing ECG assessment on or prior to Day 1, 0.5 hours prior to dose from assessment on Day 2 and Day 22. The outlying QTcF intervals were defined using the criteria: change from baseline in mean QTcF interval >30 milliseconds
Percentage of Participants With Changes in R-R Interval From Baseline
Changes in R-R interval from baseline was calculated using a time matched approach, that is change from baseline was calculated by subtracting the respective reading taken at the same nominal time on Day -1 from the reading taken on Days 1 and 21; change from baseline was calculated by subtracting the last non-missing electrocardiogram (ECG) assessment on or prior to Day 1 and 0.5 hours prior to dose for Day 2 and Day 22. Percentage of participants with changes in R-R interval from baseline was calculated as the number of participants with a change not equal to 0 across all time points divided by the number of treated participants multiplied by 100.
Pharmacokinetics: Minimum Plasma Concentration (Cmin)
Cmin for LY2334737 and its metabolite 2'2'-difluorodeoxycytidine (dFdC).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01648764
Brief Title
A Study of LY2334737 in Participants With Cancer That is Advanced and/or Has Spread
Official Title
Phase 1 Dose Escalation Study of LY2334737 Using 2 Dosing Regimens in Patients With Advanced and/or Metastatic Solid Tumors
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
September 2008 (undefined)
Primary Completion Date
November 2012 (Actual)
Study Completion Date
November 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eli Lilly and Company
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to evaluate two different dosing regimens of LY2334737 in participants with cancer that is advanced and/or has spread to other parts of the body. Information about side effects will be collected.
Detailed Description
This study will consist of a Dose Escalation Phase (Arms A and B) followed by a Dose Confirmation Phase.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Solid Tumor, Solid Tumor, Metastatic Tumor
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
73 (Actual)
8. Arms, Groups, and Interventions
Arm Title
LY2334737 - Arm A
Arm Type
Experimental
Arm Description
LY2334737 administered orally at escalating doses [40 milligrams (mg) - 200 mg] every other day for 21 days followed by 7 days without study drug (28 day treatment cycle). Participants may receive additional treatment cycles until discontinuation criterion is met.
Arm Title
LY2334737 - Arm B
Arm Type
Experimental
Arm Description
LY2334737 administered orally at escalating doses (40 mg - 200 mg) every day for 7 days followed by 7 days without study drug then repeated (28 day treatment cycle). Participants may receive additional treatment cycles until discontinuation criterion is met.
Intervention Type
Drug
Intervention Name(s)
LY2334737
Intervention Description
Administered orally
Primary Outcome Measure Information:
Title
Recommended Dose for Phase 2 Studies
Description
Recommended Phase 2 dose was determined by maximum tolerated dose (MTD). The MTD was the highest dose level at which <2 out of 6 participants experienced a dose-limiting toxicity (DLT) in Cycle 1. DLT was an adverse event (AE) during Cycle 1 that was likely related to LY2334737 and fulfilled any of the following criteria: Common Terminology Criteria for Adverse Events (CTCAE) ≥Grade 3 nonhematological (except nausea/vomiting controlled with treatment); Grade 3 neutropenia with fever or any Grade 4 neutropenia with or without fever; Grade 3 thrombocytopenia with ≥Grade 2 bleeding or Grade 4 thrombocytopenia with or without bleeding; A recovery period longer than 14 days from last dose of LY2334737 to values allowing Cycle 2 to start; Other significant drug-related toxicity deemed by investigator to be dose limiting or that caused the participant to withdraw from the study. Pharmacokinetics and pharmacodynamics (PK/PD) were also taken into consideration for Phase 2 recommended dose.
Time Frame
Baseline up to 28 days postdose in Cycle 1 (28-day cycle)
Secondary Outcome Measure Information:
Title
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for LY2334737
Description
AUC over the dosing interval (AUC0-Ƭ) of LY2334737 for Arm A (single dose) is 0 to 48 hours postdose. AUC0-Ƭ of LY2334737 for Arm B (multiple doses) is 0 to 24 hours postdose and AUC time 0 to infinity (AUC0-∞) for LY2334737.
Time Frame
Cycle 1 Day 1 (C1 D1): 0.5, 1.5, 2, 3.5, 7 24 hours postdose; Cycle 1 Day 21 (C1 D21): predose, 0.5, 2, 3 to 4, 7, 24 hours postdose of 28-day cycle
Title
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for 2'2'-Difluorodeoxycytidine (dFdC)
Description
AUC over the dosing interval (AUC0-Ƭ) of dFdC (a metabolite of LY2334737) for Arm A (following a single dose of LY2334737) AUC0-Ƭ is 0-48 hours postdose, Arm B (following multiple doses of LY2334737) AUC 0-Ƭ is 0-24 hours postdose and AUC from time 0 to infinity (AUC0-∞).
Time Frame
Cycle 1 Day 1 (C1 D1): 0.5, 1.5, 2, 3.5, 7 24 hours post dose; Cycle 1 Day 21 (C1 D21): predose, 0.5, 2, 3 to 4, 7, 24 hours post dose of 28-day cycle
Title
Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) for Difluorodeoxyuridine (dFdU)
Description
Daily AUC from time 0 to 24 hours (AUC 0-24) of dFdU (a metabolite of LY2334737) for Arm A (single dose of LY2334737) and Arm B (multiple doses of LY2334737).
Time Frame
Cycle 1 Day 1 (C1 D1): 0.5, 1.5, 2, 3.5, 7 24 hours postdose; Cycle 1 Day 21 (C1 D21): predose, 0.5, 2, 3 to 4, 7, 24 hours postdose of 28-day cycle
Title
Pharmacokinetics: Maximum Plasma Concentration (Cmax)
Description
Cmax for LY2334737 and its metabolites 2'2'-difluorodeoxycytidine (dFdC) and difluorodeoxyuridine (dFdU).
Time Frame
Cycle 1 Day 1 (C1 D1): 0.5, 1.5, 2, 3.5, 7 24 hours postdose; Cycle 1 Day 21 (C1 D21): predose, 0.5, 2, 3 to 4, 7, 24 hours postdose of 28-day cycle
Title
Number of Participants With Best Overall Response (BOR)
Description
Response defined using Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria. Complete Response defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Partial Response defined as ≥30% decrease in sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD) defined as ≥20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions, or appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Stable Disease was defined as small changes that did not meet above criteria and unknown defined as response status was not known. The BOR was the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).
Time Frame
Baseline to measured disease progression up to 33 weeks
Title
Progression-Free Survival (PFS)
Description
PFS was defined as the time from date of first dose to the first observation of disease progression or death due to any cause.
Due to the different tumor types, schedules and doses, the PFS was not analyzed.
Time Frame
Baseline to measured disease progression or death up to 33 weeks
Title
Percentage of Participants With Changes in QT Interval (>30 Milliseconds) From Baseline
Description
Fridericia-corrected QT (QTcF) interval corrected for heart rate was assessed using triplicate 12-lead electrocardiograms (ECGs). Change in QT interval from baseline was calculated using a time matched approach, that is change from baseline was calculated by subtracting the respective reading taken at the same nominal time on Day-1 from the reading taken on Days 1 and 21; change from baseline was calculated by subtracting the last non-missing ECG assessment on or prior to Day 1, 0.5 hours prior to dose from assessment on Day 2 and Day 22. The outlying QTcF intervals were defined using the criteria: change from baseline in mean QTcF interval >30 milliseconds
Time Frame
Day -1: 24.5 hours, 22 hours and 17 hours predose; Cycle 1 Days 1 and 21, 0.5 hours predose, 2 hours, 7 hours and 24 hours postdose (28-day cycles)
Title
Percentage of Participants With Changes in R-R Interval From Baseline
Description
Changes in R-R interval from baseline was calculated using a time matched approach, that is change from baseline was calculated by subtracting the respective reading taken at the same nominal time on Day -1 from the reading taken on Days 1 and 21; change from baseline was calculated by subtracting the last non-missing electrocardiogram (ECG) assessment on or prior to Day 1 and 0.5 hours prior to dose for Day 2 and Day 22. Percentage of participants with changes in R-R interval from baseline was calculated as the number of participants with a change not equal to 0 across all time points divided by the number of treated participants multiplied by 100.
Time Frame
Day -1: 24.5 hours, 22 hours and 17 hours predose; Cycle 1 Days 1 and 21: 0.5 hours predose, 2 hours, 7 hours and 24 hours postdose
Title
Pharmacokinetics: Minimum Plasma Concentration (Cmin)
Description
Cmin for LY2334737 and its metabolite 2'2'-difluorodeoxycytidine (dFdC).
Time Frame
Cycle 1 Day 1 (C1 D1): 0.5, 1.5, 2, 3.5, 7, 24 hours postdose; Cycle 1 Day 21 (C1 D21): predose, 0.5, 2, 3 to 4, 7, 24 hours postdose of 28-day cycle
Other Pre-specified Outcome Measures:
Title
Number of Participants With Dose-Limiting Toxicity (DLT)
Description
DLT was defined as an adverse event (AE) during Cycle 1 that was likely related to the LY2334737 and fulfilled any of the following criteria: Common Terminology Criteria for Adverse Events (CTCAE) ≥Grade 3 nonhematological (except nausea/vomiting controlled with treatment); Grade 3 neutropenia with fever or any Grade 4 neutropenia with or without fever; Grade 3 thrombocytopenia with ≥ Grade 2 bleeding or Grade 4 thrombocytopenia; with or without bleeding A recovery period longer than 14 days from the last dose of LY2334737 to values allowing Cycle 2 to start; other significant drug-related toxicity deemed by the investigator to be dose limiting or that caused the participant to withdraw from the study.
Time Frame
Cycle 1 (28-day cycle)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Diagnosis of advanced and/or metastatic cancer (including lymphoma) for which no treatment of higher priority exists
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Estimated life expectancy of more than 12 weeks
Have discontinued all previous therapies for cancer for at least 30 days (6 weeks for mitomycin-C or nitrosoureas) and recovered from acute effects of therapy
Have discontinued radiotherapy more than one week before enrolling in the study and have recovered from the acute effects of therapy
Have adequate organ function
Follow your doctor's directions and live close enough to the study site so you can continue to go to the clinic for follow-up
Are willing and able to swallow capsules and follow study procedures
Have given written informed consent prior to any study-specific procedures
Males and females with reproductive potential should use medically approved contraceptive precautions during the study and for 6 months following the last dose of study drug
Females with child-bearing potential must have had a negative urine or serum pregnancy test 7 days prior to the first dose of study drug
Exclusion Criteria:
Have gastrointestinal diseases or prior surgery that may interfere with the absorption of medication taken by mouth
Females who are pregnant or lactating
Symptomatic central nervous system malignancy or metastasis
Known positive test results in human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb)
Liver cirrhosis or chronic hepatitis
Acute or chronic leukemia
Are currently receiving treatment with valproic acid (VPA) and its derivatives, or if you have a history of intolerance to VPA
Known hypersensitivity to gemcitabine
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
Organizational Affiliation
Eli Lilly and Company
Official's Role
Study Director
Facility Information:
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19111
Country
United States
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Clichy
ZIP/Postal Code
92118
Country
France
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
City
Nürnberg
ZIP/Postal Code
90419
Country
Germany
12. IPD Sharing Statement
Learn more about this trial
A Study of LY2334737 in Participants With Cancer That is Advanced and/or Has Spread
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